T cell-driven inflammation is a key component of several inflammatory airway diseases, including chronic obstructive pulmonary disease (COPD). A recently identified subset of effector T cells, known as T helper type (Th)-17 cells, has been implicated in the pathogenesis of a number of chronic inflammatory conditions, including COPD. Yet, the role of these cells in chronic airway inflammation remains to be elucidated. Th17 cells secrete the cytokines IL-17 and IL-22 which act on surrounding epithelial and endothelial cells, as well as on resident antigen presenting cells, to elicit production of inflammatory cytokines and chemokines, leading to the recruitment of other inflammatory cells, including neutrophils. Differentiation of Th17 cells in the gut lumen has been closely linked to specific microbiota. However, whether the microbiome of other mucosal sites, such as the airways, is intimately linked to differentiation of Th17 cells at other sites is unknown. Airway neutrophilia is a common feature of COPD that parallels decline in lung function. Furthermore, COPD patients often present with high bacterial burden in the lower airways and the extent of airway colonization is closely associated with reduced lung function and enhanced co-morbidity. Our recent analysis of a cohort of smokers, a population that is at high risk of developing COPD, revealed that a distinct repertoire of airway microbiota is closely associated with elevated levels of pro-inflammatory cytokines and increased Th17 cells in the airways. Based on the paradigm that gut microbiota are critical in shaping the mucosal immune response in diseases such as inflammatory bowel disease, and in light of our preliminary studies, we hypothesize that airway microbiota plays a central role in directing the differentiation of Th17 cells, which in turn promoe chronic airway neutrophilia in COPD. To examine this, we will assess airway microbiota, cytokines and T cell populations in a unique cohort of asymptomatic smokers and smokers that develop COPD. To interrogate the connection between airway microbiota, Th17 cells and airway inflammation further we will take advantage of our novel mouse model that develops airway inflammation reminiscent of chronic airway inflammation seen in COPD. We will use this mouse model and a cigarette smoke inhalation model to gain mechanistic insight into the contribution of Th17-produced IL-17 and IL-22 to airway neutrophilia, mucus production, remodeling, emphysema and associated abnormalities in lung function. Furthermore, we will take advantage of our germ free facility to examine the contribution of airway microbiota and bacterial products in driving Th17-mediated airway inflammation and pathogenesis of COPD. We will accomplish this through re-introduction of bacterial communities or heat-killed bacteria into the recently rederived germ-free mice. These studies will provide new insight into the link between microbiota, Th17-mediated airway inflammation and COPD pathogenesis.